Vol 73, No 6 (2023)
Review paper
Published online: 2023-10-27

open access

Page views 484
Article views/downloads 382
Get Citation

Connect on Social Media

Connect on Social Media

Wnt pathways in focus – mapping current clinical trials across the cancer spectrum

Renata Pacholczak-Madej1, Paulina Frączek2, Klaudia Skrzypek3, Mirosława Püsküllüoğlu4
Nowotwory. Journal of Oncology 2023;73(6):370-380.

Abstract

The Wnt pathway has a pivotal function in tissue development and homeostasis, overseeing cell growth or differentiation. Aberrant Wnt signalling pathways have been associated with the pathogenesis of diverse malignancies, influencing cell proliferation, differentiation, cancer stem cell renewal, the tumour microenvironment and thereby significantly im­pacting tumour development and therapeutic responsiveness. Promisingly, current research underscores the potential therapeutic value of targeting Wnt pathways, particularly canonical Wnt/β-catenin signalling, in the context of numerous cancer types. Key constituents of the Wnt pathway, such as the Wnt/receptor, β-catenin degradation or transcription complexes, have been focal points for interventions in preclinical studies. To comprehend potential therapeutic strate­gies, we conduct an analysis of ongoing clinical trials that specifically aim to target components of the Wnt pathways across a diverse spectrum of cancer types. By scrutinizing these trials, including their respective phases, targeted pa­tient populations ,and observed outcomes, this review provides a consolidated overview of the current translational landscape of Wnt-targeted therapies, thus offering a roadmap for future research endeavours.

Review article
Tumor biology

NOWOTWORY Journal of Oncology

2023, volume 73, number 6, 370–380

DOI: 10.5603/njo.97607

© Polskie Towarzystwo Onkologiczne

ISSN: 0029–540X, e-ISSN: 2300-2115

www.nowotwory.edu.pl

Wnt pathways in focus – mapping current clinical trials across the cancer spectrum

Renata Pacholczak-Madej1Paulina Frączek2Klaudia Skrzypek3Mirosława Püsküllüoğlu4
1Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland
2Department of Oncology, University Hospital in Krakow, Poland
3Department of Transplantation, Institute of Pediatrics, Jagiellonian University Medical College, Faculty of Medicine, Krakow, Poland
4Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow Branch, Krakow, Poland
The Wnt pathway has a pivotal function in tissue development and homeostasis, overseeing cell growth or differentiation. Aberrant Wnt signalling pathways have been associated with the pathogenesis of diverse malignancies, influencing cell proliferation, differentiation, cancer stem cell renewal, the tumour microenvironment and thereby significantly impacting tumour development and therapeutic responsiveness. Promisingly, current research underscores the potential therapeutic value of targeting Wnt pathways, particularly canonical Wnt/β-catenin signalling, in the context of numerous cancer types. Key constituents of the Wnt pathway, such as the Wnt/receptor, β-catenin degradation or transcription complexes, have been focal points for interventions in preclinical studies. To comprehend potential therapeutic strategies, we conduct an analysis of ongoing clinical trials that specifically aim to target components of the Wnt pathways across a diverse spectrum of cancer types. By scrutinizing these trials, including their respective phases, targeted patient populations ,and observed outcomes, this review provides a consolidated overview of the current translational landscape of Wnt-targeted therapies, thus offering a roadmap for future research endeavours.
Key words: cancer, clinical trials, Wnt signalling pathways, targeted therapy

How to cite:

Pacholczak-Madej R, Frączek P, Skrzypek K, Püsküllüoğlu M. Wnt pathways in focus – mapping current clinical trials across the cancer spectrum. NOWOTWORY J Oncol 2023; 73: 370–380.

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

Introduction

Cancer is one of the main causes of death worldwide [1]. While chemotherapy remains the backbone of systemic treatment for both the radically and palliatively treated cancer patient population, new options including a growing number of molecularly targeted drugs have entered the market with new and new indications [2]. The journey from the initial discovery of a compound to its approval by regulatory bodies like the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) is an extensive process. It initiates with preclinical evaluations and advances through a multi-stage series of clinical trials involving human subjects. A significant proportion of compounds displaying promise in the preclinical phase ultimately do not achieve the specified endpoints during the clinical trial phases [3–6]. Figure 1 succinctly outlines this intricate progression.

Figure 1. Sequential stages of drug discovery and registration [3–6]

There are numerous signaling pathways abrupted in cancer cells that have been already used as targets for different therapeutic strategies including kinase inhibitors (Kis), monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), drugs’ nanoforms [2]. Activation of these pathways can induce alterations in cell survival capabilities, metabolic processes, cellular proliferation, differentiation, thereby impacting the tumor microenvironment. Moreover, it plays a role in angiogenesis, epithelial to mesenchymal transition, and the formation of metastases [7–10]. Among the numerous pathways with key components that are established targets for treatment, prominent examples comprise epidermal growth factor receptor/RAS/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase (EGFR/RAS/RAF), human epidermal growth factor receptor 2 (HER2), sonic hedgehog (SHH), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and protein kinase B/mammalian target of rapamycin (AKT/mTOR). It is noteworthy that the elements of these pathways often intersect during signal transduction [7–10]. Wnt represents a fundamental pathway crucial in both embryonic development and the onset of tumorigenesis [11]. Presently, there are no registered drugs specifically targeting the elements of this pathway, despite it presenting an apparent target for innovative anticancer agents. The objective of this review is to delve into the prospects of translating elements of the Wnt pathway from preclinical research to clinical applications. Through meticulous examination of these trials, encompassing their phases, targeted population, and the active drug studied, the review furnishes a comprehensive summary of the present translational panorama concerning therapies directed at the Wnt pathways.

Canonical and non-canonical Wnt signalling

The Wnt pathway plays a pivotal role in numerous developmental and homeostatic processes. Aberrations within this pathway have been implicated in a spectrum of pathological conditions, including cancers. The intricate balance and regulation of the Wnt pathway underscore its paramount importance in cellular homeostasis, presenting a potential target for therapeutic interventions in malignancies and other diseases.

There are in fact several signaling pathways that can be activated with the elements of Wnt. The canonical pathway is the most well-known (fig. 2). At the core of this pathway lies β-catenin, a key protein acting as a linchpin orchestrating downstream signaling events. Two other pathways are planar cell polarity (PCP) and calcium-related pathways [11–16].

Figure 2. Canonical Wnt pathway inactive (on the left-hand side) and active (on the right-hand side) (created with BioRender) [11–16] APC – adenomatous polyposis coli; CBP – CREB-binding protein; CK1-α – casein kinase 1-alpha; GSK-3β – glycogen synthase kinase 3-beta; LEF – lymphoid enhancer factor; LRP – low-density lipoprotein receptor-related protein; TCF – T cell factor

Wnt proteins are categorized into canonical and noncanonical types, instigating both respective pathways by engaging Frizzled (FZD) receptors (tab. I). Frizzled receptors require a co-receptor, low-density lipoprotein receptor-related protein 5/6 (LRP5/6) for canonical signaling, and receptor tyrosine kinase-like orphan receptor 1/2 (ROR1/2) for non-canonical signaling, to transmit signals effectively [11–17].

Table I. Canonical and non-canonical elements of the Wnt family [11, 16]

Pathway

Proteins

canonical

Wnt / β-catenin

Wnt1, Wnt2, Wnt3, Wnt3a, Wnt8a, Wnt8b, Wnt10a, Wnt10b

non canonical

PCP, Wnt / Ca2+

Wnt3, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt11

Within the canonical pathway, upon activation, Wnt binding disrupts the β-catenin destruction complex, preventing the phosphorylation of β-catenin by GSK-3β, thereby averting its proteasomal degradation. Key components of the destruction complex include:

  • adenomatous polyposis coli (APC),
  • glycogen synthase kinase 3-beta (GSK-3β),
  • axin, casein kinase 1-alpha (CK1-α).

The accumulation of β-catenin in the cytoplasm enables its translocation into the nucleus, where it forms complexes with various transcription factors, primarily lymphoid enhancer factor/T-cell factor (LEF/TCF), initiating the transcription of vital Wnt/β-catenin target genes such as: cMyc, cyclin D1 (CCND1), and VEGF or programmed death-ligand 1 (PD-L1) [11–16].

Non-canonical Wnt pathways are Wnt / PCP and Wnt-cyclic guanosine monophosphate / calcium ion (Wnt-cGMP/Ca2+) signaling. The targets for these non-canonical pathways can include matrix metalloproteinases (MMPs) or AKT/mTOR. These pathways are believed to exert an influence on processes such as epithelial-mesenchymal transition (EMT), cell migration, cell metabolism, chemo-resistance, or the formation of metastases [11, 16, 17].

Preclinical and clinical cancer studies regarding Wnt elements

Inhibition of the Wnt pathway represents an interesting and promising molecular target for novel anticancer therapies in various malignancies. Many new molecules have been investigated in preclinical studies or in clinical trials mainly phase 1 (tab. II). Some of them have reached phase 2 clinical trials in the treatment of solid malignancies, as well as hematologic, but recruitment is ongoing or the results of those trials are expected to be soon published. An interesting approach represents the combination of Wnt inhibitors with chemotherapy of targeted therapies PD-1/PD-L1 inhibitors (nivolumab / pembrolizumab) or EGFR inhibitors (cetuximab).

Table II. Agents inhibiting the Wnt pathway which are under investigation. Complied on the basis of clinicaltrials.gov as of April 2023, unless otherwise specified

Name of agent

Mechanism of action

Development stage

Indications

Reference

Name of agent

Mechanism of action

Development stage

Indications

Reference

PKF115–584, CGP049090, PKF222–815, PKF118–310, PKF118–744, ZTM000990

β-catenin TCF antagonists

preclinical

colorectal cancer, breast cancer

[18, 19]

iCRT3, iCRT5, iCRT14

β-catenin TCF antagonists

preclinical

colorectal cancer, triple negative breast cancer

[20, 21]

BC21

β-catenin TCF antagonists

preclinical

colorectal cancer

[22]

FH535

β-catenin TCF antagonists

preclinical

triple negative breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma

[23, 24]

CWP232228

β-catenin TCF antagonists

preclinical

breast cancer

[25]

ICG-001

β-catenin / CBP inhibitor

preclinical

triple negative breast cancer

[26]

CG0009

glycogen synthase kinase 3α/β inhibitor

preclinical

breast cancer

[27]

niclosamide

inhibition the binding of a WNT ligand to LRP5/6 receptors

preclinical

breast cancer

[28]

salinomycin

inhibition the binding of a WNT ligand to LRP5/6 receptors

preclinical

breast cancer, prostate cancer, chronic lymphocytic leukemia

[29, 30]

LGK974 (WNT974)

inhibitor of the WNT-receptor complex (porcupine inhibitor)

phase 1 clinical trial, recruiting

pancreatic cancer, BRAF-mutant colorectal cancer, melanoma, triple negative breast cancer, head and neck squamous-cell cancer, cervical squamous-cell cancer, esophageal squamous-cell cancer, lung squamous-cell cancer

[31]

phase 1 and 2 clinical trial + cetuximab, completed

BRAF-mutant metastatic colorectal cancer

[32]

preclinical

Ewing sarcoma

[33]

preclinical

clear cell, renal cell carcinoma

[34]

ETC-1922159

inhibitor of the WNT-receptor complex (porcupine inhibitor)

phase I clinical trial

+/– pembrolizumab, recruiting

advanced solid tumors

[35]

CGX1321

Inhibitor of the WNT-receptor complex (porcupine inhibitor)

phase I clinical trial

+/– pembrolizumab or encorafenib + cetuximab,

recruiting

advanced gastrointestinal tumors

[36]

phase 1 clinical trial, recruiting

advanced gastrointestinal tumors

[37]

RXC004

inhibitor of the WNT-receptor complex (porcupine inhibitor)

phase 1 clinical trial

+/– nivolumab,

recruiting

advanced solid tumors

[38]

phase 2 clinical trial,

recruiting

advanced solid tumors

[39]

phase 2 clinical trial +/–nivolumab, recruiting

colorectal cancer

[40]

XNW7201

inhibitor of the WNT-receptor complex (porcupine inhibitor)

phase 1 clinical trial, active, not recruiting

advanced solid tumors

[41]

OMP-18R5 (vantictumab)

inhibitor of the WNT-receptor complex

(antibody against WNT family proteins – namely FZD1, FZD2, FZD5, FZD7 and FZD8)

phase 1 clinical trial, completed

advanced solid tumors

[42]

phase 1 clinical trial +/– nab-paklitaxel and gemcitabine, completed

advanced pancreatic cancer

[43, 44]

phase 1b clinical trial + docetaxel, completed

non-small cell lung cancer

[45]

phase 1b clinical trial, completed

metastatic breast cancer

[46]

OMP-54F28

(ipafricept)

inhibitor of the WNT-receptor complex

(antibody against WNT family proteins – namely FZD 8 receptor)

phase 1 clinical trial, completed

advanced solid tumors

[47, 48]

phase 1 clinical trial + sorafenib, completed

hepatocellular cancer

[49]

phase 1 clinical trial + paclitaxel and carboplatin, completed

ovarian cancer

[50, 51]

phase 1 clinical trial + nab-paclitaxel and gemcitabine, completed

pancreatic cancer

[52]

OTSA101

inhibitor of the WNT-receptor complex

(antibody against Wnt family proteins – namely FZD 10 receptor)

phase 1 clinical trial, recruiting

synovial sarcoma

[53]

NVP-TNKS656

β-catenin-destruction complex inhibitors, namely

tankyrase inhibitors (PARPs family)

preclinical

colorectal cancer

[54]

XAV939

β-catenin-destruction complex inhibitors, namely tankyrase inhibitors (PARPs family)

preclinical

breast cancer

[55]

PRI-724

inhibition of the CBP and β-catenin interaction

phase 1a/1b clinical trial,

terminated

advanced solid tumors

[56, 57]

phase 1 clinical trial + gemcitabine, completed

pancreatic cancer

[58, 59]

phase 1 and 2 clinical trial, completed

acute myeloid leukemia, chronic myeloid leukemia

[60]

CWP232291

inhibitor of the Wnt pathway, induction of apoptosis via activation of caspases

phase 1 clinical trial, completed

refractory acute myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic syndrome, myelofibrosis

[61, 62]

phase 1 clinical trial +/ lenalidomide, dexamethasone, completed

multiple myeloma

[63, 64]

phase 1 and 2 clinical trial, active, not recruiting

acute myeloid leukemia

[65]

DKN-01

monoclonal antibody, inhibitor of the DKK1 activity, a modulator of Wnt / β-catenin signaling

phase 1 clinical trial +/– paclitaxel or pembrolizumab, completed

esophageal cancer gastroesophageal junction cancer, gastric adenocarcinoma with Wnt signaling alterations

[66, 67]

phase 1 clinical trial + gemcitabine/cisplatine, completed

carcinoma primary to the intra- or exta-hepatic biliary system or gallbladder

[68, 69]

phase 1b/2a clinical trial +/– docetaxel, recruiting

prostate cancer

[70, 71]

phase 1 and 2 clinical trial +/– sorafenib, recruiting

advanced liver cancer

[72]

phase 2 clinical trial + nivolumab, recruiting

advanced biliary tract cancer

[73]

phase 2 clinical trial +/– paclitaxel, completed

endometrial cancer, uterine cancer, ovarian cancer, carcinosarcoma

[74]

phase 2 clinical trial + tiselizumab +/– chemotherapy, recruiting

gastric cancer, gastroesophageal cancer

[75]

phase 1 clinical trial, completed

multiple myeloma, solid tumors,
non-small-cell lung cancer

[76, 77]

phase 1 clinical trial + lenalidomide/dexamethasone,

completed

relapsed or refractory multiple myeloma

[77]

phase 1 and 2 clinical trial

+ atezolizumab, recruiting

metastatic esophageal cancer, metastatic gastric cancer

[78]

Foxy-5

WNT5A-mimicking peptide

phase 1 clinical trials, completed

breast cancer, colon cancer, prostate cancer

[79, 80]

phase 2 clinical trial, recruiting

colon cancer (neoadjuvant setting)

[81]

UC-961

(cirmtuzumab)

monoclonal antibody against ROR1 of the non-canonical Wnt pathway

phase 2 clinical trial + docetaxel,

not yet recruiting

metastatic castration resistant prostate cancer

[82]

phase 1 clinical trial, completed

relapsed or refractory chronic lymphocytic leukemia

[83, 84]

phase 1 and 2 clinical trial + ibrutinib, active, not recruiting

B-cell lymphoid malignancies

[85, 86]

phase 2 clinical trial, recruiting

chronic lymphocytic leukemia, consolidation after venetoclaxs

[87]

phase 1 clinical trial

+ paclitaxel, active, not recruiting

breast cancer

[88]

PRI-724

CBP / β-catenin antagonist

phase 2 clinical trial

+ FOLFOX and bevacizumab, withdrawn

metastatic colorectal cancer

[89]

phase 1 clinical trial

+ gemcitabine, completed

advanced pancreatic cancer

[90, 91]

phase 1 and 2 clinical trial, completed

acute myeloid leukemia, chronic myeloid leukemia

[92]

phase 1 clinical trial, terminated

advanced solid tumors

[93]

PF-06647020 (cofetuzumab pelidotin)

monoclonal antibody against PTK7 – inhibition of non-canonical Wnt pathway

phase 1 clinical trial + gedatolisib, completed

triple negative breast cancer

[94–96]

phase 1 clinical trial, completed

non-small cell lung cancer

[97, 98]

phase 1 clinical trial, completed

advanced solid tumors

[99, 100]

GDC-0449 (vismodegib)

inhibitor of the hedgehog pathway

FDA and EMA registered

metastatic/locally advanced basal cell carcinoma

[101, 102]

numerous clinical trials phase 1–3

advanced solid tumors (also advanced breast cancer) hematologic malignancies

#

LDE225

(sonidegib)

inhibitor of the hedgehog pathway

FDA and EMA registered

metastatic/locally advanced basal cell carcinoma

[103, 104]

numerous clinical trials phase 1–3

advanced solid tumors (also advanced breast cancer)
hematologic malignancies

#

itraconazole

antifungal medication, inhibitor of the hedgehog pathway

numerous clinical trials phase 1–3

prostate cancer, lung cancer, ovarian cancer, esophageal cancer, multiple myeloma, solid malignancies

#

PF-04449913

(glasdegib)

inhibitor of the hedgehog pathway

phase 1 and 2 clinical trials

hematologic malignancies

#

phase 1 clinical trial, completed

solid tumors

[105, 106]

phase 1 and 2 clinical trial

+ temozolomide, active, not recruiting

glioblastoma

[107]

IPI-926

(patidegib)

inhibitor of the hedgehog pathway

phase 1 clinical trial, completed

basal cell carcinoma

[108]

phase 1 and 2 clinical trial + gemcitabine, completed

pancreatic cancer

[109, 110]

phase 1 + FOLIFIRINOX, completed

pancreatic cancer

[111, 112]

phase 1 clinical trial, completed

solid tumor malignancies

[113, 114]

phase 1 clinical trial + cetuximab, completed

head and neck cancer

[115, 116]

phase 2 clinical trial, completed

unresectable chondrosarcoma

[117]

LY2940680

inhibitor of the hedgehog pathway

phase 2 clinical trial, completed

solid tumor malignancies

[118]

ENV-101

inhibitor of the hedgehog pathway

phase 2 clinical trial, recruiting

advanced solid tumors harboring PTCH1 loss of function mutations

[119]

phase 1 clinical trial, completed

breast cancer, colon cancer, cholangiocarcinoma, soft tissue sarcoma

[120]

phase 1 and 2 clinical trial, completed

esophageal or gastroesophageal junction cancer

[121]

lycopene

naturally synthesized carotenoid (an active component of red fruits and vegetables) suppression of β-catenin nuclear expression

phase 2 clinical trial,

active, not recruiting

skin toxicity in patients with colorectal carcinoma treated with panitumumab

[122]

preclinical

gastric cancer, breast cancer

[123, 124]

artesunate

antimalarial drug – suppression of Wnt pathway by downregulation of c-Myc and cyclin D1

phase 2 clinical trial, active, not recruiting

stage II/III colorectal cancer (pre-operative treatment)

[125, 126]

phase 1 clinical trial, completed

advanced solid tumors

[127, 128]

phase 1 clinical trial, completed

metastatic breast cancer

[129, 130]

resveratol

non-flavonoid polyphenol suppression of Wnt pathway by decreasing the expression of β-catenin and cyclin D1

phase 1 clinical trial, completed

colon cancer

[131, 132]

preclinical

breast cancer, gastric cancer

[133, 134]

quercetin

flavonoid (component of onion, red grapes, lettuce, tomato). Inhibition of the Notch1, PI3K/AKT and β-catenin signaling pathways

preclinical

breast cancer, ovarian cancer, B-cell lymphomas

[135–137]

Katoh and Katoh divided Wnt-targeted agents into pan-Wnt inhibitors (like porcupine inhibitors), canonical (like β-catenin protein-protein inhibitor) and non-canonical (like ROR1 inhibitors) [12]. However, there is a significant group of compounds that modulate the signal indirectly or influence Wnt signalling by interfering with other pathways (like SHH). β-catenin itself plays an important role as a signal transducer in other pathways including trophoblast cell surface antigen 2 (TROP-2) [138].

Current trials, as shown in table II, involve drugs acting on numerous levels of these signaling pathways:

  • Outside the cancer cell / on the cell membrane level: Wnt-mimicking agents [79, 80]; monoclonal antibody against ROR1 (cirmtuzumab) [82–86]; Wnt proteins / receptors inhibitors like: porcupine inhibitors LGK974, ETC-1922159, CGX1321, RXC004, XNW7201 [31–41] or FZD inhibitors (vantictumab, ipafricept, OTSA101) [42–53]. Porcupine serves as a vital enzyme within the Wnt signaling pathway, aiding in the palmitoylation of Wnt proteins. This alteration is pivotal for the appropriate secretion of Wnt proteins and the initiation of the Wnt signaling pathway [139]. Monoclonal antibodies against protein tyrosine kinase 7 (PTK7) can also be included into that group. PTK-7 is a transmembrane receptor protein that has been implicated in the regulation of the Wnt signaling pathway (cofetuzumab pelidotin) [94–102].
  • In the cytoplasm: dikkopf-1 (DKK1) modulators (DKN-01) [66–71]. Functioning as an extracellular antagonist, DKK1 binds to LRP5/6 co-receptors, interrupting their engagement with Wnt ligands and obstructing the activation of the canonical Wnt pathway. This impediment leads to a halt in the accumulation and nuclear movement of β-catenin [140].
  • Within the nucleus e.g. inhibiting the target canonical pathway genes [125, 126] or CREB-binding protein (CBP) / β-catenin inhibitors (ICG-001, PRI-724, PRI-724 [26, 5660, 8996). CBP serves as a coactivator for transcription within the canonical Wnt pathway, collaborating with transcription factors such as β-catenin. It amplifies the transcription of Wnt target genes by modifying chromatin structure through the acetylation of histones [141].
  • Within other signaling pathways that interact with Wnt including SHH (vismodegib, sonidegib, itraconazole, glasdegib, patidegib, LY2940680, ENV-101) as the most visible example [101–121].

While compounds acting on β-catenin degradation complex show activity in preclinical studies, their clinical activity has not been confirmed yet (NVP-TNKS656, XAV939) [54, 55]. Numerous limitations accompany the development of Wnt pathway inhibitors. They include: the non-obvious role of Wnt elements in cancer development and progression, its role in physiological processes, its complexity. Notably, WNT inhibitors have the potential to serve not only in cancer therapy but also in a supportive capacity to mitigate treatment-related toxicity [11–17, 142].

Numerous novel molecules have undergone scrutiny in either preclinical investigations or clinical trials. A portion of these compounds has progressed to phase 2 clinical trials, marking the mid-point in the translational process depicted in figure 1.

Conclusions

The precise equilibrium and meticulous regulation observed in the Wnt pathway underline its paramount importance in maintaining cellular homeostasis, thereby delineating it as a promising focal point for therapeutic interventions directed at malignancies. The Wnt pathway branches into canonical and noncanonical categories, each instigating distinctive signaling cascades through specific receptor engagement. A comprehensive understanding of these pathways and their constituent elements is imperative for discerning their potential therapeutic ramifications. Presently, preclinical and clinical inquiries into Wnt elements are progressing, presenting an enticing trajectory for the development of novel anticancer therapies. However, the intricate nature of Wnt signaling, its dual role in both disease and physiological homeostasis, and the complexities surrounding its inhibitors do pose formidable challenges. The number of trials and the variety of molecular targets related to Wnt pathways, as well as different cancer indications within the patient population (tab. II) provide grounds for optimism regarding the possibility of advancing beyond the early phases of clinical trials in the journey from bench to bedside (fig. 1).

Article information and declarations

Author contributions

Renata Pacholczak-Madej study conception and design, material collection, analysis and interpretation of results: all authors; manuscript preparation.

Mirosława Püsküllüoğlu study conception and design, material collection, analysis and interpretation of results: all authors; manuscript preparation.

Paulina Frączek manuscript critical review.

Klaudia Skrzypek manuscript critical review.

All authors have approved the final version of the paper.

Funding

None declared

Conflict of interest

None declared

Mirosława Püsküllüoğlu

Maria Sklodowska-Curie National Research Institute of Oncology

Krakow Branch

Department of Clinical Oncology

Ul. Garncarska 11

31-115 Krakow, Poland

e-mail: mira.puskulluoglu@gmail.com

Received: 27 Sep 2023
Accepted: 17 Oct 2023

References

  1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin. 2022; 72(1): 733, doi: 10.3322/caac.21708, indexed in Pubmed: 35020204.
  2. Ługowska IE. Handbook of Targeted Therapies and Precision Oncology. ESMO Press, Lugano 2022.
  3. Choudhari AS, Mandave PC, Deshpande M, et al. Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice. Front Pharmacol. 2019; 10: 1614, doi: 10.3389/fphar.2019.01614, indexed in Pubmed: 32116665.
  4. Hughes JP, Rees S, Kalindjian SB, et al. Principles of early drug discovery. Br J Pharmacol. 2011; 162(6): 12391249, doi: 10.1111/j.1476-5381.2010.01127.x, indexed in Pubmed: 21091654.
  5. Berdigaliyev N, Aljofan M. An overview of drug discovery and development. Future Med Chem. 2020; 12(10): 939947, doi: 10.4155/fmc-2019-0307, indexed in Pubmed: 32270704.
  6. Kaushik I, Ramachandran S, Prasad S, et al. Drug rechanneling: A novel paradigm for cancer treatment. Semin Cancer Biol. 2021; 68: 279290, doi: 10.1016/j.semcancer.2020.03.011, indexed in Pubmed: 32437876.
  7. You M, Xie Z, Zhang N, et al. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduct Target Ther. 2023; 8(1): 196, doi: 10.1038/s41392-023-01442-3, indexed in Pubmed: 37164974.
  8. Lang BJ, Prince TL, Okusha Y, et al. Heat shock proteins in cell signaling and cancer. Biochim Biophys Acta Mol Cell Res. 2022; 1869(3): 119187, doi: 10.1016/j.bbamcr.2021.119187, indexed in Pubmed: 34906617.
  9. Borlongan MC, Wang H. Profiling and targeting cancer stem cell signaling pathways for cancer therapeutics. Front Cell Dev Biol. 2023; 11: 1125174, doi: 10.3389/fcell.2023.1125174, indexed in Pubmed: 37305676.
  10. Yip HY, Papa A. Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments. Cells. 2021; 10(3), doi: 10.3390/cells10030659, indexed in Pubmed: 33809714.
  11. Wilusz M, Majka M. Role of the Wnt/beta-catenin network in regulating hematopoiesis. Arch Immunol Ther Exp (Warsz). 2008; 56(4): 257266, doi: 10.1007/s00005-008-0029-y, indexed in Pubmed: 18726147.
  12. Katoh M, Katoh M. WNT signaling and cancer stemness. Essays Biochem. 2022; 66(4): 319331, doi: 10.1042/EBC20220016, indexed in Pubmed: 35837811.
  13. Pamarthy S, Kulshrestha A, Katara GK, et al. The curious case of vacuolar ATPase: regulation of signaling pathways. Mol Cancer. 2018; 17(1): 41, doi: 10.1186/s12943-018-0811-3, indexed in Pubmed: 29448933.
  14. Martin-Orozco E, Sanchez-Fernandez A, Ortiz-Parra I, et al. WNT Signaling in Tumors: The Way to Evade Drugs and Immunity. Front Immunol. 2019; 10: 2854, doi: 10.3389/fimmu.2019.02854, indexed in Pubmed: 31921125.
  15. Zhang Ya, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol. 2020; 13(1): 165, doi: 10.1186/s13045-020-00990-3, indexed in Pubmed: 33276800.
  16. Chen Y, Chen Z, Tang Y, et al. The involvement of noncanonical Wnt signaling in cancers. Biomed Pharmacother. 2021; 133: 110946, doi: 10.1016/j.biopha.2020.110946, indexed in Pubmed: 33212376.
  17. Xiao Q, Chen Z, Jin X, et al. The many postures of noncanonical Wnt signaling in development and diseases. Biomed Pharmacother. 2017; 93: 359369, doi: 10.1016/j.biopha.2017.06.061, indexed in Pubmed: 28651237.
  18. Lepourcelet M, Chen YNP, France DS, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell. 2004; 5(1): 91102, doi: 10.1016/s1535-6108(03)00334-9, indexed in Pubmed: 14749129.
  19. Hallett RM, Kondratyev MK, Giacomelli AO, et al. Small molecule antagonists of the Wnt/β-catenin signaling pathway target breast tumor-initiating cells in a Her2/Neu mouse model of breast cancer. PLoS One. 2012; 7(3): e33976, doi: 10.1371/journal.pone.0033976, indexed in Pubmed: 22470504.
  20. Gonsalves FC, Klein K, Carson BB, et al. An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt/wingless signaling pathway. Proc Natl Acad Sci U S A. 2011; 108(15): 59545963, doi: 10.1073/pnas.1017496108, indexed in Pubmed: 21393571.
  21. Bilir B, Kucuk O, Moreno CS. Wnt signaling blockage inhibits cell proliferation and migration, and induces apoptosis in triple-negative breast cancer cells. J Transl Med. 2013; 11: 280, doi: 10.1186/1479-5876-11-280, indexed in Pubmed: 24188694.
  22. Tian W, Han X, Yan M, et al. Structure-based discovery of a novel inhibitor targeting the β-catenin/Tcf4 interaction. Biochemistry. 2012; 51(2): 724731, doi: 10.1021/bi201428h, indexed in Pubmed: 22224445.
  23. Handeli S, Simon JA. A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities. Mol Cancer Ther. 2008; 7(3): 521529, doi: 10.1158/1535-7163.MCT-07-2063, indexed in Pubmed: 18347139.
  24. Iida J, Dorchak J, Lehman JR, et al. FH535 inhibited migration and growth of breast cancer cells. PLoS One. 2012; 7(9): e44418, doi: 10.1371/journal.pone.0044418, indexed in Pubmed: 22984505.
  25. Jang GB, Hong IS, Kim RJ, et al. Wnt/β-Catenin Small-Molecule Inhibitor CWP232228 Preferentially Inhibits the Growth of Breast Cancer Stem-like Cells. Cancer Res. 2015; 75(8): 16911702, doi: 10.1158/0008-5472.CAN-14-2041, indexed in Pubmed: 25660951.
  26. Sulaiman A, McGarry S, Li Li, et al. Dual inhibition of Wnt and Yes-associated protein signaling retards the growth of triple-negative breast cancer in both mesenchymal and epithelial states. Mol Oncol. 2018; 12(4): 423440, doi: 10.1002/1878-0261.12167, indexed in Pubmed: 29316250.
  27. Kim HMi, Kim CS, Lee JH, et al. CG0009, a novel glycogen synthase kinase 3 inhibitor, induces cell death through cyclin D1 depletion in breast cancer cells. PLoS One. 2013; 8(4): e60383, doi: 10.1371/journal.pone.0060383, indexed in Pubmed: 23565238.
  28. Londoño-Joshi AI, Arend RC, Aristizabal L, et al. Effect of niclosamide on basal-like breast cancers. Mol Cancer Ther. 2014; 13(4): 800811, doi: 10.1158/1535-7163.MCT-13-0555, indexed in Pubmed: 24552774.
  29. Lu W, Li Y. Salinomycin suppresses LRP6 expression and inhibits both Wnt/β-catenin and mTORC1 signaling in breast and prostate cancer cells. J Cell Biochem. 2014; 115(10): 17991807, doi: 10.1002/jcb.24850, indexed in Pubmed: 24905570.
  30. Lu D, Choi MY, Yu J, et al. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A. 2011; 108(32): 1325313257, doi: 10.1073/pnas.1110431108, indexed in Pubmed: 21788521.
  31. A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands. https://clinicaltrials.gov/ct2/show/NCT01351103 (12.04.2023).
  32. Study of WNT974 in Combination With LGX818 and Cetuximab in Patients With BRAF-mutant Metastatic Colorectal Cancer (mCRC) and Wnt Pathway Mutations. https://clinicaltrials.gov/ct2/show/NCT02278133 (12.04.2023).
  33. Hayashi M, Baker A, Goldstein SD, et al. Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma. Oncotarget. 2017; 8(45): 7826578276, doi: 10.18632/oncotarget.19432, indexed in Pubmed: 29108227.
  34. Li J, Wu G, Xu Y, et al. Porcupine Inhibitor LGK974 Downregulates the Wnt Signaling Pathway and Inhibits Clear Cell Renal Cell Carcinoma. Biomed Res Int. 2020; 2020: 2527643, doi: 10.1155/2020/2527643, indexed in Pubmed: 32104684.
  35. A Study to Evaluate the Safety and Tolerability of ETC-1922159 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumours. https://clinicaltrials.gov/ct2/show/NCT02521844 (25.11.2022).
  36. CGX1321 in Subjects With Advanced Solid Tumors and CGX1321 With Pembrolizumab or Encorafenib + Cetuximab in Subjects With Advanced GI Tumors (Keynote 596). https://clinicaltrials.gov/ct2/show/NCT02675946 (25.11.2022).
  37. Phase 1 Dose Escalation Study of CGX1321 in Subjects With Advanced Gastrointestinal Tumors. https://clinicaltrials.gov/ct2/show/NCT03507998 (25.11.2022).
  38. Study to Evaluate the Safety and Tolerability of RXC004 in Advanced Malignancies. https://clinicaltrials.gov/ct2/show/NCT03447470 (25.11.2022).
  39. A Study to Assess RXC004 Efficacy in Advanced Solid Tumours After Progression on Standard of Care (SoC) Therapy (PORCUPINE2). https://clinicaltrials.gov/ct2/show/NCT04907851 (25.11.2022).
  40. A Study to Assess Efficacy of RXC004 +/- Nivolumab in Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer After Progression on Standard of Care (SOC). https://clinicaltrials.gov/ct2/show/NCT04907539 (25.11.2022).
  41. Phase 1 Study to Evaluate the Safety, Tolerability and Pharmacokinetic Profile of XNW7201 in Subjects With Advanced Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT03901950 (25.11.2022).
  42. Smith D, Rosen L, Chugh R, et al. First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors. Journal of Clinical Oncology. 2013; 31(15_suppl): 25402540, doi: 10.1200/jco.2013.31.15_suppl.2540.
  43. Davis SL, Cardin DB, Shahda S, et al. A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer. Invest New Drugs. 2020; 38(3): 821830, doi: 10.1007/s10637-019-00824-1, indexed in Pubmed: 31338636.
  44. A Study of Vantictumab (OMP-18R5) in Combination With Nab-Paclitaxel and Gemcitabine in Previously Untreated Stage IV Pancreatic Cancer. https://clinicaltrials.gov/ct2/show/NCT02005315 (25.11.2022).
  45. A Study of Vantictumab (OMP-18R5) in Combination With Docetaxel in Patients With Previously Treated NSCLC. https://clinicaltrials.gov/ct2/show/NCT01957007 (25.11.2022).
  46. Diamond JR, Becerra C, Richards D, et al. Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer. Breast Cancer Res Treat. 2020; 184(1): 5362, doi: 10.1007/s10549-020-05817-w, indexed in Pubmed: 32803633.
  47. Jimeno A, Gordon M, Chugh R, et al. A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2017; 23(24): 74907497, doi: 10.1158/1078-0432.CCR-17-2157, indexed in Pubmed: 28954784.
  48. A Dose Escalation Study of OMP-54F28 in Subjects With Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT01608867 (25.11.2022).
  49. Dose Escalation Study of OMP-54F28 in Combination With Sorafenib in Patients With Hepatocellular Cancer. https://clinicaltrials.gov/ct2/show/NCT02069145 (25.11.2022).
  50. Moore KN, Gunderson CC, Sabbatini P, et al. A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Gynecol Oncol. 2019; 154(2): 294301, doi: 10.1016/j.ygyno.2019.04.001, indexed in Pubmed: 31174889.
  51. Dose Escalation Study of OMP-54F28 in Combination With Paclitaxel and Carboplatin in Patients With Recurrent Platinum-Sensitive Ovarian Cancer. https://clinicaltrials.gov/ct2/show/NCT02092363 (25.11.2022).
  52. Dotan E, Cardin DB, Lenz HJ, et al. Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer. Clin Cancer Res. 2020; 26(20): 53485357, doi: 10.1158/1078-0432.CCR-20-0489, indexed in Pubmed: 32694153.
  53. Phase I Study of Radiolabeled OTSA101-DTPA in Patients With Relapsed or Refractory Synovial Sarcoma. https://clinicaltrials.gov/ct2/show/NCT04176016 (25.11.2022).
  54. Arqués O, Chicote I, Puig I, et al. Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer. Clin Cancer Res. 2016; 22(3): 644656, doi: 10.1158/1078-0432.CCR-14-3081, indexed in Pubmed: 26224873.
  55. Bao R, Christova T, Song S, et al. Inhibition of tankyrases induces Axin stabilization and blocks Wnt signalling in breast cancer cells. PLoS One. 2012; 7(11): e48670, doi: 10.1371/journal.pone.0048670, indexed in Pubmed: 23144924.
  56. El-Khoueiry A, Ning Y, Yang D, et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. J Clin Oncol. 2013; 31(15_suppl): 25012501, doi: 10.1200/jco.2013.31.15_suppl.2501.
  57. Safety and Efficacy Study of PRI-724 in Subjects With Advanced Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT01302405 (25.11.2022).
  58. Ko A, Chiorean E, Kwak E, et al. Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX. J Clin Oncol. 2016; 34(15_suppl): e15721e15721, doi: 10.1200/jco.2016.34.15_suppl.e15721.
  59. Safety and Efficacy Study of PRI-724 Plus Gemcitabine in Subjects With Advanced or Metastatic Pancreatic Adenocarcinoma. https://clinicaltrials.gov/ct2/show/NCT01764477 (25.11.2022).
  60. Safety and Efficacy Study of PRI-724 in Subjects With Advanced Myeloid Malignancies. https://clinicaltrials.gov/ct2/show/NCT01606579 (25.11.2022).
  61. Lee JH, Faderl S, Pagel JM, et al. Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. Blood Adv. 2020; 4(9): 20322043, doi: 10.1182/bloodadvances.2019000757, indexed in Pubmed: 32396615.
  62. Phase I Clinical Study of CWP232291 in Acute Myeloid Leukemia Patients. https://clinicaltrials.gov/ct2/show/NCT01398462 (25.11.2022).
  63. Yoon SS, Manasanch E, Min C, et al. Novel phase 1a/1b dose-finding study design of CWP232291 (CWP291) in relapsed or refractory myeloma (MM). J Clin Oncol. 2017; 35(15_suppl): TPS8058TPS8058, doi: 10.1200/jco.2017.35.15_suppl.tps8058.
  64. Clinical Study of CWP232291 in Relapsed or Refractory Myeloma Patients. https://clinicaltrials.gov/ct2/show/NCT02426723 (25.11.2022).
  65. Clinical Study of CWP232291 in Acute Myeloid Leukemia Patients. https://clinicaltrials.gov/ct2/show/NCT03055286 (25.11.2022).
  66. Klempner SJ, Bendell JC, Villaflor VM, et al. Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers. Mol Cancer Ther. 2021; 20(11): 22402249, doi: 10.1158/1535-7163.MCT-21-0273, indexed in Pubmed: 34482288.
  67. A Study of DKN-01 in Combination With Paclitaxel or Pembrolizumab. https://clinicaltrials.gov/ct2/show/NCT02013154 (25.11.2022).
  68. Goyal L, Sirard C, Schrag M, et al. Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer. Clin Cancer Res. 2020; 26(23): 61586167, doi: 10.1158/1078-0432.CCR-20-1310, indexed in Pubmed: 32878766.
  69. Goyal L, Sirard C, Schrag M, et al. Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer. Clin Cancer Res. 2020; 26(23): 61586167, doi: 10.1158/1078-0432.CCR-20-1310, indexed in Pubmed: 32878766.
  70. Wise DR, Schneider JA, Armenia J, et al. International SU2C/PCF Prostate Cancer Dream Team. Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer. JCO Precis Oncol. 2020; 4, doi: 10.1200/PO.20.00097, indexed in Pubmed: 33015525.
  71. A Parallel Arm Phase 1b/2a Study of DKN-01 as Monotherapy or in Combination With Docetaxel for the Treatment of Advanced Prostate Cancer With Elevated DKK1. https://clinicaltrials.gov/ct2/show/NCT03837353 (25.11.2022).
  72. DKN-01 Inhibition in Advanced Liver Cancer. https://clinicaltrials.gov/ct2/show/NCT03645980 (25.11.2022).
  73. Study of the Combination of DKN-01 and Nivolumab in Previously Treated Patients With Advanced Biliary Tract Cancer (BTC). https://clinicaltrials.gov/ct2/show/NCT04057365 (25.11.2022).
  74. A Study of DKN-01 as a Monotherapy or in Combination With Paclitaxel in Patients With Recurrent Epithelial Endometrial or Epithelial Ovarian Cancer or Carcinosarcoma. https://clinicaltrials.gov/ct2/show/NCT03395080 (25.11.2022).
  75. A Study of DKN-01 in Combination With Tislelizumab ± Chemotherapy in Patients With Gastric or Gastroesophageal Cancer. https://clinicaltrials.gov/ct2/show/NCT04363801 (25.11.2022).
  76. Edenfield W, Richards D, Vukelja S, et al. A phase 1 study evaluating the safety and efficacy of DKN-01, an investigational monoclonal antibody (Mab) in patients (pts) with advanced non-small cell lung cancer. J Clin Oncol. 2014; 32(15_suppl): 80688068, doi: 10.1200/jco.2014.32.15_suppl.8068.
  77. A Study of DKN-01 in Multiple Myeloma or Advanced Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT01457417 (25.11.2022).
  78. WaKING: Wnt and checKpoint INhibition in Gastric Cancer. https://clinicaltrials.gov/ct2/show/NCT04166721 (25.11.2022).
  79. Soerensen P, Andersson T, Buhl U, et al. Phase I dose-escalating study to evaluate the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of Foxy-5 in patients with metastatic breast, colorectal, or prostate cancer. J Clin Oncol. 2014; 32(15_suppl): TPS1140TPS1140, doi: 10.1200/jco.2014.32.15_suppl.tps1140.
  80. Phase I Study to Evaluate Safety, Tolerability, Anti-Tumour Activity and PK Profiles of Foxy-5 in Metastatic Breast, Colon or Prostate Cancer. https://clinicaltrials.gov/ct2/show/NCT02020291 (25.11.2022).
  81. Foxy-5 as Neo-Adjuvant Therapy in Subjects With Wnt-5a Low Colon Cancer. https://clinicaltrials.gov/ct2/show/NCT03883802 (25.11.2022).
  82. Study of Docetaxel Combined With Cirmtuzumab in Metastatic Castration Resistant Prostate Cancer. https://clinicaltrials.gov/ct2/show/NCT05156905 (25.11.2022).
  83. Extension Study of UC-961 (Cirmtuzumab) for Patients With Chronic Lymphocytic Leukemia Treated Previously With UC-961. https://clinicaltrials.gov/ct2/show/NCT02860676 (25.11.2022).
  84. UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia. https://clinicaltrials.gov/ct2/show/NCT02222 688 (25.11.2022).
  85. Lee H, Choi M, Siddiqi T, et al. Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL). J Clin Oncol. 2021; 39(15_suppl): 75567556, doi: 10.1200/jco.2021.39.15_suppl.7556.
  86. A Study of Cirmtuzumab and Ibrutinib in Patients With B-Cell Lymphoid Malignancies. https://clinicaltrials.gov/ct2/show/NCT03088878 (25.11.2022).
  87. Cirmtuzumab Consolidation for Treatment of Patients With Detectable CLL on Venetoclax. https://clinicaltrials.gov/ct2/show/NCT04501939 (25.11.2022).
  88. Study of Cirmtuzumab and Paclitaxel for Metastatic or Locally Advanced, Unresectable Breast Cancer. https://clinicaltrials.gov/ct2/show/NCT02776917 (25.11.2022).
  89. Combination Chemotherapy and Bevacizumab With or Without PRI-724 in Treating Patients With Newly Diagnosed Metastatic Colorectal Cancer. https://clinicaltrials.gov/ct2/show/NCT02413853 (25.11.2022).
  90. Ko A, Chiorean E, Kwak E, et al. Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-
    -line therapy after FOLFIRINOX or FOLFOX.
    J Clin Oncol. 2016; 34(15_suppl): e15721e15721, doi: 10.1200/jco.2016.34.15_suppl.e15721.
  91. Safety and Efficacy Study of PRI-724 Plus Gemcitabine in Subjects With Advanced or Metastatic Pancreatic Adenocarcinoma. https://clinicaltrials.gov/ct2/show/NCT01764477 (25.11.2022).
  92. Safety and Efficacy Study of PRI-724 in Subjects With Advanced Myeloid Malignancies. https://clinicaltrials.gov/ct2/show/NCT01606579 (25.11.2022).
  93. El-Khoueiry A, Ning Y, Yang D, et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. J Clin Oncol. 2013; 31(15_suppl): 25012501, doi: 10.1200/jco.2013.31.15_suppl.2501.
  94. Damelin M, Bankovich A, Bernstein J, et al. A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. Sci Transl Med. 2017; 9(372), doi: 10.1126/scitranslmed.aag2611, indexed in Pubmed: 28077676.
  95. Katoh M. Antibody-drug conjugate targeting protein tyrosine kinase 7, a receptor tyrosine kinase-like molecule involved in WNT and vascular endothelial growth factor signaling: effects on cancer stem cells, tumor microenvironment and whole-body homeostasis. Ann Transl Med. 2017; 5(23): 462, doi: 10.21037/atm.2017.09.11, indexed in Pubmed: 29285495.
  96. An Initial Safety Study of Gedatolisib Plus PTK7-ADC for Metastatic Triple-negative Breast Cancer. https://clinicaltrials.gov/ct2/show/NCT03243331 (25.11.2022).
  97. Radovich M, Solzak JP, Hancock BA, et al. Abstract OT3-06-02: An initial safety study of gedatolisib plus PTK7-ADC for metastatic triple-negative breast cancer. Cancer Research. 2019; 79(4_Supplement): OT3-06-02-OT3-0602, doi: 10.1158/1538-7445.sabcs18-ot3-06-02.
  98. An Efficacy and Safety Study of Cofetuzumab Pelidotin in Participants With PTK7-Expressing, Recurrent Non-Small Cell Lung Cancer. https://clinicaltrials.gov/ct2/show/NCT04189614?term=Cofetuzumab+pelidotin&draw=2&rank=1 (25.11.2022).
  99. Maitland ML, Sachdev JC, Sharma MR, et al. First-in-Human Study of PF-06647020 (Cofetuzumab Pelidotin), an Antibody-Drug Conjugate Targeting Protein Tyrosine Kinase 7, in Advanced Solid Tumors. Clin Cancer Res. 2021; 27(16): 45114520, doi: 10.1158/1078-0432.CCR-20-3757, indexed in Pubmed: 34083232.
  100. A Study Of PF-06647020 For Adult Patients With Advanced Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT02222922 (25.11.2022).
  101. Sekulic A, Migden MR, Basset-Seguin N, et al. ERIVANCE BCC Investigators. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017; 17(1): 332, doi: 10.1186/s12885-017-3286-5, indexed in Pubmed: 28511673.
  102. CHMP. VISMODEGIB- ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS. https://www.ema.europa.eu/en/documents/product-information/erivedge-epar-product-information_en.pdf.
  103. Dummer R, Guminksi A, Gutzmer R, et al. Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study. Br J Dermatol. 2020; 182(6): 13691378, doi: 10.1111/bjd.18552, indexed in Pubmed: 31545507.
  104. CHMP. SONIDEGIB- ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS. https://www.ema.europa.eu/en/documents/product-information/odomzo-epar-product-information_en.pdf.
  105. Wagner AJ, Messersmith WA, Shaik MN, et al. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015; 21(5): 10441051, doi: 10.1158/1078-0432.CCR-14-1116, indexed in Pubmed: 25388167.
  106. A Study Of PF-04449913 Administered Alone In Select Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT01286467 (25.05.2022).
  107. Glasdegib (PF-04449913) With Temozolomide Newly Diagnosed Glioblastoma. https://clinicaltrials.gov/ct2/show/NCT03466450 (25.05.2022).
  108. Clinical Trial of Patidegib Gel 2%, 4%, and Vehicle Applied Once or Twice Daily to Decrease the GLI1 Biomarker in Sporadic Nodular Basal Cell Carcinomas. https://clinicaltrials.gov/ct2/show/NCT02828111 (25.05.2022).
  109. Richards D, Stephenson J, Wolpin B, et al. A phase Ib trial of IPI-926, a hedgehog pathway inhibitor, plus gemcitabine in patients with metastatic pancreatic cancer. Journal of Clinical Oncology. 2012; 30(4_suppl): 213213, doi: 10.1200/jco.2012.30.4_suppl.213.
  110. A Study Evaluating IPI-926 in Combination With Gemcitabine in Patients With Metastatic Pancreatic Cancer. https://clinicaltrials.gov/ct2/show/NCT01130142 (25.05.2022).
  111. Ko AH, LoConte N, Tempero MA, et al. A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma. Pancreas. 2016; 45(3): 370375, doi: 10.1097/MPA.0000000000000458, indexed in Pubmed: 26390428.
  112. FOLFIRINOX Plus IPI-926 for Advanced Pancreatic Adenocarcinoma. https://clinicaltrials.gov/ct2/show/NCT01383538 (25.05.2022).
  113. Jimeno A, Weiss GJ, Miller WH, et al. Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res. 2013; 19(10): 27662774, doi: 10.1158/1078-0432.CCR-12-3654, indexed in Pubmed: 23575478.
  114. A Phase 1 Study of IPI-926 in Patients With Advanced and/or Metastatic Solid Tumor Malignancies. https://clinicaltrials.gov/ct2/show/NCT00761696 (25.11.2022).
  115. Bowles DW, Keysar SB, Eagles JR, et al. A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma. Oral Oncol. 2016; 53: 7479, doi: 10.1016/j.oraloncology.2015.11.014, indexed in Pubmed: 26705064.
  116. Pilot Study of Cetuximab and the Hedgehog Inhibitor IPI-926 in Recurrent Head and Neck Cancer. https://clinicaltrials.gov/ct2/show/NCT01255800 (25.11.2022).
  117. A Safety and Efficacy Study of Patients With Metastatic or Locally Advanced (Unresectable) Chondrosarcoma. https://clinicaltrials.gov/ct2/show/NCT01310816 (25.11.2022).
  118. A Study of LY2940680 in Japanese Participants With Advanced Cancers. https://clinicaltrials.gov/ct2/show/NCT01919398 (25.11.2022).
  119. A Study Evaluating the Safety and Efficacy of ENV-101 (Taladegib) in Patients With Advanced Solid Tumors Harboring PTCH1 Loss of Function Mutations. https://www.clinicaltrials.gov/ct2/show/NCT05199584 (25.11.2022).
  120. A Study of LY3039478 in Participants With Advanced or Metastatic Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT02784795 (25.11.2022).
  121. Taladegib, Paclitaxel, Carboplatin, and Radiation Therapy in Treating Patients With Localized Esophageal or Gastroesophageal Junction Cancer. https://clinicaltrials.gov/ct2/show/NCT02530437 (25.11.2022).
  122. Moroni M, Pirovano M, Brugnatelli S, et al. Lycopene minimizes skin toxicity and oxidative stress in patients treated with panitumumab-containing therapy for metastatic colorectal cancer. J Funct Foods. 2021; 83: 104533, doi: 10.1016/j.jff.2021.104533.
  123. Kim M, Kim SH, Lim JW, et al. Lycopene induces apoptosis by inhibiting nuclear translocation of β-catenin in gastric cancer cells. J Physiol Pharmacol. 2019; 70(4), doi: 10.26402/jpp.2019.4.11, indexed in Pubmed: 31741457.
  124. Preet R, Mohapatra P, Das D, et al. Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC. Carcinogenesis. 2013; 34(2): 277286, doi: 10.1093/carcin/bgs351, indexed in Pubmed: 23129580.
  125. Hamoya T, Fujii G, Iizumi Y, et al. Artesunate inhibits intestinal tumorigenesis through inhibiting wnt signaling. Carcinogenesis. 2021; 42(1): 148158, doi: 10.1093/carcin/bgaa084, indexed in Pubmed: 32710739.
  126. A Safety and Effectiveness Study of Pre-operative Artesunate in Stage II/III Colorectal Cancer. https://clinicaltrials.gov/ct2/show/NCT02633098 (25.11.2022).
  127. Deeken JF, Wang H, Hartley M, et al. A phase I study of intravenous artesunate in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol. 2018; 81(3): 587596, doi: 10.1007/s00280-018-3533-8, indexed in Pubmed: 29392450.
  128. Phase I Study of Intravenous Artesunate for Solid Tumors. https://clinicaltrials.gov/ct2/show/NCT02353026 (25.11.2022).
  129. von Hagens C, Walter-Sack I, Goeckenjan M, et al. Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res Treat. 2017; 164(2): 359369, doi: 10.1007/s10549-017-4261-1, indexed in Pubmed: 28439738.
  130. Study of Artesunate in Metastatic Breast Cancer. https://clinicaltrials.gov/ct2/show/NCT00764036 (25.11.2022).
  131. Holcombe R, Holcombe R. Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Management and Research. 2009: 25, doi: 10.2147/cmr.s4544.
  132. Resveratrol for Patients With Colon Cancer. https://clinicaltrials.gov/ct2/show/NCT00256334?term=NCT00256334&draw=2&rank=1 (25.11.2022).
  133. Fu Y, Chang H, Peng X, et al. Resveratrol inhibits breast cancer stem-like cells and induces autophagy via suppressing Wnt/β-catenin signaling pathway. PLoS One. 2014; 9(7): e102535, doi: 10.1371/journal.pone.0102535, indexed in Pubmed: 25068516.
  134. Dai H, Deng HB, Wang YH, et al. Resveratrol inhibits the growth of gastric cancer via the Wnt/β-catenin pathway. Oncol Lett. 2018; 16(2): 15791583, doi: 10.3892/ol.2018.8772, indexed in Pubmed: 30008840.
  135. Reyes-Farias M, Carrasco-Pozo C. The Anti-Cancer Effect of Quercetin: Molecular Implications in Cancer Metabolism. Int J Mol Sci. 2019; 20(13), doi: 10.3390/ijms20133177, indexed in Pubmed: 31261749.
  136. Khorsandi L, Orazizadeh M, Niazvand F, et al. Quercetin induces apoptosis and necroptosis in MCF-7 breast cancer cells. Bratisl Lek Listy. 2017; 118(2): 123128, doi: 10.4149/BLL_2017_025, indexed in Pubmed: 28814095.
  137. Niazvand F, Orazizadeh M, Khorsandi L, et al. Effects of Quercetin-Loaded Nanoparticles on MCF-7 Human Breast Cancer Cells. Medicina (Kaunas). 2019; 55(4), doi: 10.3390/medicina55040114, indexed in Pubmed: 31013662.
  138. Zhao W, Jia L, Kuai X, et al. The role and molecular mechanism of Trop2 induced epithelial-mesenchymal transition through mediated β-catenin in gastric cancer. Cancer Med. 2019; 8(3): 11351147, doi: 10.1002/cam4.1934, indexed in Pubmed: 30632714.
  139. Rahimi Kalateh Shah Mohammad G, Ghahremanloo A, Soltani A, et al. Cytokines as potential combination agents with PD-1/PD-L1 blockade for cancer treatment. J Cell Physiol. 2020; 235(7-8): 54495460, doi: 10.1002/jcp.29491, indexed in Pubmed: 31970790.
  140. Jiang H, Zhang Z, Yu Y, et al. Drug Discovery of DKK1 Inhibitors. Front Pharmacol. 2022; 13: 847387, doi: 10.3389/fphar.2022.847387, indexed in Pubmed: 35355709.
  141. Yamada K, Hori Y, Inoue S, et al. E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling. Cancer Res. 2021; 81(4): 10521062, doi: 10.1158/0008-5472.CAN-20-0782, indexed in Pubmed: 33408116.
  142. Moroni M, Pirovano M, Brugnatelli S, et al. Lycopene minimizes skin toxicity and oxidative stress in patients treated with panitumumab-containing therapy for metastatic colorectal cancer. J Funct Foods. 2021; 83: 104533, doi: 10.1016/j.jff.2021.104533.